TOR (target of rapamycin) is evolutionarily conserved from yeast to humans and has a pivotal role of controlling cell growth in all cell types. There is fundamental gap in our understanding of the physiological pathways that interact with TOR and how modulating those pathways regulate lifespan and healthspan. There is an urgent need to identify the full spectrum of interactions that describes TOR activity. The long-term goal is to have a complete understanding of how TOR regulates cellular physiology. The immediate goal of this application is to use a systems approach and the budding yeast Saccharomyces cerevisiae to fill important gaps in our knowledge of TOR activity. It is the evolutionary conservation of the TOR complexes coupled with the outstanding genetic tools that are available for studying budding yeast that are central to this application. The central hypothesis i that there are physiological pathways that interact with TOR or are regulated by TOR that are unidentified and will be evolutionarily conserved from yeast to humans. The rationale is that novel pathways will be discovered using a new and under-utilized genetic approach called complex haplo-insufficiency (CHI) that generates novel information about genetic interactions. Guided by strong preliminary data, the proposed research will be guided by two specific aims: 1). Identify and characterize novel targets of TORC1 and TORC2. We will perform CHI using a novel genome-wide approach that incorporates essential and non-essential genes. We will prioritize novel interactions in yeast prioritized by human homologs and unidentified pathways or genes. We will characterize the genes in yeast and human cells 2). Identify novel rapalogs. We will use a computational approach to compare data from CHI with TORC1 to publicly available data and predict potential rapalogs by similarity in genetic interactions, concentrating on human homologs. We will characterize the potential rapalogs in yeast and human cells. The proposed research is innovative because it uses a novel genetic approach in the most tractable model organism and applies it for the first time to TOR biology. The proposed research is significant because it is expected to identify new interactions with TOR and ultimately identify compounds that can be used for medical intervention to modulate TOR activity and impact both healthspan and lifespan. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because there is an urgent need to identify the physiological pathways that interact with TOR and identify new chemical compounds that target the TOR pathway for medical intervention. Thus the research is relevant to the NIH mission and is ultimately expected to positively impact lifespan and healthspan and reduce the burdens of human disabilities.